EP2344882B1 - Urinary biomarkers for predicting long-term dialysis - Google Patents

Urinary biomarkers for predicting long-term dialysis Download PDF

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EP2344882B1
EP2344882B1 EP09816577.2A EP09816577A EP2344882B1 EP 2344882 B1 EP2344882 B1 EP 2344882B1 EP 09816577 A EP09816577 A EP 09816577A EP 2344882 B1 EP2344882 B1 EP 2344882B1
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patient
hyaluronic acid
kidney
kidney disease
kidney injury
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German (de)
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French (fr)
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EP2344882A2 (en
EP2344882A4 (en
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Kai Singbartl
John A. Kellum, Jr.
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University of Pittsburgh
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University of Pittsburgh
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/5308—Immunoassay; Biospecific binding assay; Materials therefor for analytes not provided for elsewhere, e.g. nucleic acids, uric acid, worms, mites
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/52—Use of compounds or compositions for colorimetric, spectrophotometric or fluorometric investigation, e.g. use of reagent paper and including single- and multilayer analytical elements
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2400/00—Assays, e.g. immunoassays or enzyme assays, involving carbohydrates
    • G01N2400/10—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • G01N2400/38—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence, e.g. gluco- or galactomannans, Konjac gum, Locust bean gum or Guar gum
    • G01N2400/40—Glycosaminoglycans, i.e. GAG or mucopolysaccharides, e.g. chondroitin sulfate, dermatan sulfate, hyaluronic acid, heparin, heparan sulfate, and related sulfated polysaccharides
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/34—Genitourinary disorders
    • G01N2800/347—Renal failures; Glomerular diseases; Tubulointerstitial diseases, e.g. nephritic syndrome, glomerulonephritis; Renovascular diseases, e.g. renal artery occlusion, nephropathy
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00—Chemistry: analytical and immunological testing
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00—Chemistry: analytical and immunological testing
    • Y10T436/14—Heterocyclic carbon compound [i.e., O, S, N, Se, Te, as only ring hetero atom]
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00—Chemistry: analytical and immunological testing
    • Y10T436/14—Heterocyclic carbon compound [i.e., O, S, N, Se, Te, as only ring hetero atom]
    • Y10T436/142222—Hetero-O [e.g., ascorbic acid, etc.]
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00—Chemistry: analytical and immunological testing
    • Y10T436/14—Heterocyclic carbon compound [i.e., O, S, N, Se, Te, as only ring hetero atom]
    • Y10T436/142222—Hetero-O [e.g., ascorbic acid, etc.]
    • Y10T436/143333—Saccharide [e.g., DNA, etc.]

Definitions

  • This invention is related to the field of the prevention and treatment of kidney disease.
  • the treatment of kidney disease may be tailored depending upon the need for, or expectation of, long-term dialysis.
  • prediction of long-term dialysis treatment can be determined by monitoring urine biomarkers related to the development of chronic kidney disease.
  • a normalized time course of hyaluronic acid can be used to determine whether a patient having suffered acute kidney injury will require long-term dialysis.
  • CKD Chronic kidney disease
  • a major cause of CKD is acute kidney injury (AKI), which is itself an independent predictor of morbidity and mortality and is associated with substantially increased healthcare costs, especially if dialysis (or a related kidney support technique) is required.
  • AKI acute kidney injury
  • Chronic kidney disease can develop as a result of many different factors, but most notably, genetic predisposition and/or acute kidney injury.
  • the degree of kidney injury is also associated with an incremental increase in long-term mortality.
  • Crude 1-yr case-fatality after hospital discharge can be as high as 64% for patients with severe, dialysis-requiring AKI.
  • currently used markers of kidney function/injury such as serum creatinine levels, are poor at discriminating long-term outcome of kidney disease.
  • chronic kidney disease has a high proportion of patients requiring long-term dialysis (i.e., for example, renal replacement therapy or RRT). This treatment is expensive, time consuming, and can be untoward side effects, including, but not limited to, blood vessel stenosis and/or thromobosis.
  • RRT renal replacement therapy
  • This invention is related to the field of the prevention and treatment of kidney disease.
  • the treatment of kidney disease may be tailored depending upon the need for, or expectation of, long-term dialysis.
  • prediction of long-term dialysis treatment can be determined by monitoring urine biomarkers related to the development of chronic kidney disease.
  • a normalized time course of hyaluronic acid can be used to determine whether a patient having suffered acute kidney injury will require long-term dialysis.
  • the present invention contemplates a method, comprising a) detecting persistently elevated hyaluronic acid between the first and fourteenth day starting after initiation of replacement therapy for severe kidney injury on said patient in at least two urine samples derived from a patient that exhibits an acute kidney injury; and b) predicting the patient to require long-term dialysis.
  • the method further comprises diagnosing the patient with chronic kidney disease.
  • the diagnosing occurs at least sixty days after the kidney injury.
  • the method further comprises entering the patient in a chronic kidney disease prevention program.
  • the present invention contemplates a method, comprising a) detecting persistently elevated hyaluronic acid between the first and fourteenth day starting after initiation of replacement therapy for severe kidney injury on said patient in at least two urine samples derived from a patient that exhibits acute kidney injury wherein said patient is at risk for development of chronic kidney disease; and b) predicting that said patient requires treatment to prevent chronic kidney disease.
  • the treating is initiated on day 14 after the kidney disease.
  • the present invention contemplates a method comprising: a) providing a plurality of urinary hyaluronic acid and creatinine levels from the patient, wherein the levels are obtained over time; b) constructing a urinary hyaluronic acid level time course, wherein the time course is normalized against the urinary creatinine levels; and c) predicting chronic kidney disease development under conditions such that said normalized hyaluronic acid levels steadily increase over said time course.
  • the predicting includes long-term renal replacement therapy (i.e., for example, dialysis).
  • biomarker refers to any biological compound related to the progressive development of chronic kidney disease.
  • a biomarker may comprise hyaluronic acid, or any of its metabolites or derivatives.
  • prognosis refers to a medical conclusion based upon an analysis any biomarker that provides information regarding the progression of medical conditions including, but not limited to, chronic kidney disease or cardiovascular disease. Such information includes, but is not limited to the determination of a long-term dialysis risk.
  • predicting refers to a method of forming a prognosis, wherein a medically trained person analyzes biomarker information.
  • chronic kidney disease refers to a medical condition wherein exemplary symptoms may include, but are not limited to, hyperphosphatemia (i.e., for example, > 4.6 mg/dl) or low glomerular filtration rates (i.e., for example, ⁇ 90 ml/minute per 1.73 m 2 of body surface).
  • hyperphosphatemia i.e., for example, > 4.6 mg/dl
  • low glomerular filtration rates i.e., for example, ⁇ 90 ml/minute per 1.73 m 2 of body surface.
  • many CKD patients may have normal serum phosphate levels in conjunction with a sustained reduction in glomerular filtration rate for 3 or more months, or a normal GFR in conjunction with sustained evidence of a structural abnormality of the kidney.
  • patients diagnosed with chronic kidney disease are placed on hemodialysis to maintain normal blood homeostasis (i.e., for example, urea or phosphate levels).
  • chronic kidney disease refers to a medical condition wherein a patients has either i) a sustained reduction in GFR ⁇ 60 mi/min per 1.73 m 2 of body surface for 3 or more months; or ii) a structural or functional abnormality of renal function for 3 or more months even in the absence of a reduced GFR.
  • Structural or anatomical abnormalities of the kidney could be defined as but not limited to persistent microalbuminuria or proteinuria or hematuria or presence of renal cysts.
  • asymptomatic refers to a patient and/or subject that does not have CKD, wherein a CKD symptom includes having a reduced glomerular filtration rate (i.e., for example, between approximately 70 - 89 ml/min per 1.73 m 2 of body surface) for less than three months.
  • kidney filtration rate refers to a measurement capable of determining kidney function (infra). In general, normal glomerular filtration rates range between approximately 120 - 90 ml/minute per 1.73 m2 of body surface. Compromised kidney function is assumed when glomerular filtration rates are less than 90 ml/minute per 1.73 m2 of body surface. Kidney failure is probable when glomerular filtration rates fall below approximately 30 ml/minute per 1.73 m2 of body surface. Dialysis is frequently initiated when glomerular filtration rates fall below approximately 15 ml/minute per 1.73 m2 of body surface.
  • renal failure refers to any acute (sudden) or chronic loss of the ability of the kidneys to remove waste and concentrate urine without losing electrolytes.
  • biological sample refers to any substance derived from a living organism.
  • a sample may be derived from blood as a urine sample, serum sample, a plasma sample, and or a whole blood sample.
  • a sample may be derived from a tissue collected, for example, by a biopsy.
  • tissue sample may comprise, for example, kidney tissue, vascular tissue and/or heart tissue.
  • a biological sample may also comprise body fluids including, but not limited to, urine, saliva, or perspiration.
  • reaction refers to any substance employed to produce a chemical reaction so as to detect, measure, produce, etc., other substances.
  • This invention is related to the field of the prevention and treatment of kidney disease.
  • the treatment of kidney disease may be tailored depending upon the need for, or expectation of, long-term dialysis.
  • prediction of long-term dialysis treatment can be determined by monitoring urine biomarkers related to the development of chronic kidney disease.
  • a normalized time course of hyaluronic acid can be used to determine whether a patient having suffered acute kidney injury will require long-term dialysis.
  • kidneys are located in the flank (back of the upper abdomen at either side of the spinal column). They are deep within the abdomen and are protected by the spine, lower rib cage, and the strong muscles of the back. This location protects the kidneys from many external forces. They are well-padded for a reason -- kidneys are highly vascular organs, which means that they have a large blood supply. If injury occurs, severe bleeding may result.
  • Kidneys may be injured by damage to the blood vessels that supply or drain them. This may be in the form of aneurysm, arteriovenous fistula, arterial blockage, or renal vein thrombosis. The extent of bleeding depends on the location and the degree of injury. Kidneys may also bleed profusely if they are damaged centrally (on the inside) -- this is a life-threatening injury. Fortunately, most kidney injuries caused by blunt trauma occur peripherally, only causing bruising of the kidney (usually a self-limiting process).
  • kidney diseases such as angiomyolipoma (benign tumor), ureteropelvic junction obstruction (congenital or acquired UPJ Obstruction), and other disorders -- are more susceptible to kidney injuries and more likely to have serious complications if they occur.
  • Other causes of kidney injury and bleeding are medical procedures.
  • Kidney biopsies, nephrostomy tube placements, or other surgeries can cause an abnormal connection between an artery and vein (arteriovenous fistula). This is usually a self-limiting problem, but close observation is usually needed. Damage to the kidney can also disrupt the urinary tract, causing leakage of the urine from the kidney.
  • kidneys Each kidney filters about 1700 liters of blood per day and concentrates fluid and waste products into about 1 liter of urine per day. Because of this, the kidneys receive more exposure to toxic substances in the body than almost any other organ. Therefore, they are highly susceptible to injury from toxic substances.
  • Analgesic nephropathy is one of the most common types of toxic damage to the kidney. Exposure to lead, cleaning products, solvents, fuels, or other nephrotoxic chemicals (those which can be toxic to the kidney) can damage kidneys. Excessive buildup of body waste products, such as uric acid (that can occur with gout or with treatment of bone marrow, lymph node, or other disorders) can also damage the kidneys.
  • Inflammation irritation with swelling and presence of extra immune cells
  • immune responses to medications, infection, or other disorders may also injure the structures of the kidney, usually causing various types of glomerulonephritis or acute tubular necrosis (tissue death).
  • Autoimmune disorders may also damage the kidneys. Damage to the kidney may result in short-term damage with minimal or no symptoms. Alternately, it can be life-threatening because of bleeding and associated shock, or it may result in acute renal failure or chronic renal failure.
  • Ureteral injuries injuries to the tubes which carry urine from the kidneys to the bladder
  • RPF retroperitoneal fibrosis
  • retroperitoneal sarcomas or metastatic lymph node positive cancers.
  • Medical therapies such as OB/GYN surgeries, prior radiation or chemotherapy, and previous abdominopelvic surgeries
  • Acute (sudden) kidney failure is the sudden loss of the ability of the kidneys to remove waste and concentrate urine without losing electrolytes.
  • kidney damage There are many possible causes of kidney damage. They include, but are not limited to, Decreased blood flow, which may occur with extremely low blood pressure caused by trauma, surgery, serious illnesses, septic shock, hemorrhage, burns, or dehydration, Acute tubular necrosis (ATN), Infections that directly injury the kidney such as acute pyelonephritis or septicemia, Urinary tract obstruction (obstructive uropathy), Autoimmune kidney disease such as interstitial nephritis or acute nephritic syndrome, Disorders that cause clotting within the thin blood vessels of the kidney, Idiopathic thrombocytopenic thrombotic purpura (ITTP), Transfusion reaction, Malignant hypertension, Scleroderma, Hemolytic-uremic syndrome, Disorders of childbirth, such as bleeding placenta abruptio
  • Symptoms of acute kidney failure may include, but are not limited to, Decrease in amount of urine (oliguria), Urination stops (anuria), Excessive urination at night, Ankle, feet, and leg swelling, Generalized swelling, fluid retention, Decreased sensation, especially in the hands or feet, Decreased appetite, Metallic taste in mouth, Persistent hiccups, Changes in mental status or mood, Agitation, Drowsiness, Lethargy, Delirium or confusion, Coma, Mood changes, Trouble paying attention, Hallucinations, Slow, sluggish, movements, Seizures, Hand tremor (shaking), Nausea or vomiting, may last for days, Bruising easily, Prolonged bleeding, Nosebleeds, Bloody stools, Flank pain (between the ribs and hips), Fatigue, Breath odor, or High blood pressure.
  • ESRD end-stage renal disease
  • Chronic renal failure usually occurs over a number of years as the internal structures of the kidney are slowly damaged. In the early stages, there may be no symptoms. In fact, progression may be so slow that symptoms do not occur until kidney function is less than one-tenth of normal.
  • Chronic renal failure results in an accumulation of fluid and waste products in the body, leading to a build up of nitrogen waste products in the blood (azotemia) and general ill health. Most body systems are affected by chronic renal failure.
  • Initial symptoms may include, but are not limited to, Fatigue, Frequent hiccups, General ill feeling, Generalized itching (pruritus), Headache, Nausea, vomiting, or Unintentional weight loss.
  • later symptoms may include, but are not limited to, Blood in the vomit or in stools, Decreased alertness, including drowsiness, confusion, delirium, orcoma, Decreased sensation in the hands, feet, or other areas, Easy bruising or bleeding, Increased or decreased urine output, Muscle twitching or cramps, Seizures, or White crystals in and on the skin (uremic frost).
  • Circulating levels of cytokines and other inflammation markers are markedly elevated in patients with chronic renal failure. This could be caused by increased generation, decreased removal, or both. However, it is not well established to what extent renal function per se contributes to the uremic proinflammatory milieu. Relationships between inflammation and glomerular filtration rate (GFR) were reported in 176 patients (age, 52 +/- 1 years; GFR, 6.5 +/-0.1 mL/min) close to the initiation of renal replacement therapy. Pecoits-Filho et al., Associations between circulating inflammatory markers and residual renal function in CRF patients. Am J Kidney Dis. 2003 Jun;41(6):1212-8 .
  • circulating levels of high-sensitivity C-reactive protein hsCRP
  • tumor necrosis factor-alpha TNF-alpha
  • IL-6 interleukin-6
  • neopterin circulating levels of high-sensitivity C-reactive protein
  • patients subsequently were subdivided into two groups according to median GFR (6.5 mL/min).
  • Dialysis i.e., for example, renal replacement therapy
  • peritoneal dialysis may filter waste by using the peritoneal membrane inside the abdomen.
  • the abdomen is filled with special solutions that help remove toxins.
  • the solutions remain in the abdomen for a time and then are drained out.
  • This form of dialysis can be performed at home, but must be done every day.
  • hemodialysis may be performed by circulating the blood through special filters outside the body. The blood flows across a filter, along with solutions that help remove toxins.
  • Dialysis uses special ways of accessing the blood in the blood vessels.
  • the access can be temporary or permanent.
  • Temporary access takes the form of dialysis catheters -- hollow tubes placed in large veins that can support acceptable blood flows. Most catheters are used in emergency situations for short periods of time. However, catheters called tunneled catheters can be used for prolonged periods of time, often weeks to months.
  • Permanent access is created by surgically joining an artery to a vein. This allows the vein to receive blood at high pressure, leading to a thickening of the vein's wall. This vein can handle repeated puncture and also provides excellent blood flow rates.
  • the connection between an artery and a vein can be made using blood vessels (an arteriovenous fistula, or AVF) or a synthetic bridge (arteriovenous graft, or AVG).
  • Blood is diverted from the access point in the body to a dialysis machine.
  • the blood flows counter-current to a special solution called the dialysate.
  • the chemical imbalances and impurities of the blood are corrected and the blood is then returned to the body.
  • the purpose of dialysis is to assist kidney functions including, filters for the blood, removing waste products, regulating body water, maintaining electrolyte balance, or maintaining blood pH remains between 7.35 and 7.45. Further, dialysis may replace some of the functions for kidneys that aren't working properly that would otherwise result in the death of a patient.
  • Dialysis is most often used for patients who have kidney failure, but it can also quickly remove drugs or poisons in acute situations. This technique can be life saving in people with acute or chronic kidney failure.
  • the present invention contemplates a urinary hyaluronic acid (HA) biomarker to predict recovery of renal function after acute kidney injury (AKI).
  • HA urinary hyaluronic acid
  • identifying the biomarker provides patient stratification to tailor treatment intensity thereby preventing unnecessary long-term complications.
  • the present invention contemplates a method comprising predicting long-term prognosis of AKI early in the disease process.
  • the method predicts long-term dialysis when urinary HA is persistently elevated between D1 - D14 after after initiation of replacement therapy for severe acute kidney injury.
  • the method predicts long-term dialysis when urinary HA is persistently elevated between D1 - D14 after initiation of replacement therapy for severe acute kidney injury.
  • the long-term dialysis comprises at least sixty (60) days after kidney injury. In one embodiment, the long-term dialysis comprises at least sixty (60) days after kidney disease diagnosis.
  • AKI survival was correlated with a urinary hyaluronic acid (HA) biomarker.
  • HA i.e., for example, hyaluronan or hyaluronate
  • HA comprises a non-sulfated glycosaminoglycan, and is believed widely distributed throughout connective, epithelial, and neural tissues.
  • HA is also believed to be one of several components within the extracellular matrix and may be involved in tissue repair and remodeling by mediating cell proliferation and migration, synthesis and degradation of extracellular matrix. For example, fragmented HA has been observed to accumulate during tissue injury and may stimulate the expression of inflammatory genes by a variety of immune cells at the injury site. Further, impaired clearance of HA has been seen to result in persistent inflammation.
  • a biomarker to predict a non-recovery of renal function, wherein dialysis-dependence is in excess of sixty (60) days.
  • Non-recovery of renal function may comprise biomarker elevation above its initial value for at least fourteen (14) days.
  • Biomarker prediction may be supported by a receiver operating characteristic (ROC) analysis.
  • ROC analysis may provide calculations including, but not limited to, area under fitted curve and/or trapezoidal (Wilcoxon) area.
  • Hyaluronic acid also known in the art as hyaluronate and hyaluronan, and abbreviated as HA
  • HA hyaluronate and hyaluronan
  • A is present ubiquitously in various types of biological material, including both bacteria and animals.
  • HA is found in high concentrations in umbilical cords, vitreous humor of the eyes, cartilage and synovial fluid. Small amounts of HA are present in CSF, lymph, blood, serum and urine. Levels of HA have been associated with diseases such as rheumatoid arthritis, liver cirrhosis, and Wilms' tumor. HA is associated with non-specific tumors in general, but its use has not been applied heretofore to the discovery, therapy and management of particular clinical tumors. HA has been known to play a role in several pathophysiological conditions including cancer.
  • HA levels have been shown to be elevated in certain animal tumor models (e.g., rabbit V2 carcinoma, Knudson et al., The role and regulation of tumor associated hyaluronan. In: The Biology of Hyaluronan (J. Whelan, ed.), pp. 150-169, New York, Wiley Chichister (Ciba Foundation Symposium 143), 1989 ) and human cancers (e.g., lung, Wilms' tumor, breast, etc., Knudson et al., ibid.). In tumor tissues, HA supports tumor cell adhesion and migration and also offers some protection against immune surveillance.
  • animal tumor models e.g., rabbit V2 carcinoma, Knudson et al., The role and regulation of tumor associated hyaluronan. In: The Biology of Hyaluronan (J. Whelan, ed.), pp. 150-169, New York, Wiley Chichister (Ciba Foundation Symposium 143), 1989
  • the HA-HAase test can be an effective adjunct to cystoscopy for monitoring bladder carcinoma recurrence. With over 90% sensitivity and 86% accuracy, the HA-HAase test can be an effective adjunct to cystoscopy for monitoring bladder carcinoma recurrence. A false-positive HA-HAase test carries a significant risk of recurrence within five months. Thus, it is possible that a combination of biochemical tests can effectively monitor bladder carcinoma recurrence, which may allow a minimum 50% reduction in the number of surveillance cystoscopy procedures.
  • Urinary hyaluronic acid may be determined by first collecting voided (clean-catch) urine specimens that are stored at -20° C until assayed.
  • the HA assay may be based upon an ELISA plate based assay for hyaluronan using biotinylated proteoglycan G1 domain (HA-binding) region. Fosang et al. Matrix, 10:306-313 (1990 ).
  • the assay may be modified by using a 96-well microtiter plates coated with human umbilical cord HA (25 ⁇ g/ml) that are incubated with serial dilutions of urine specimens in phosphate buffer saline (PBS) +0.05% Tween 20 (PBS+Tween), and a biotinylated bovine nasal cartilage HA-binding protein (1 ⁇ g/ml). Following incubation at room temperature for 16 h, the wells were washed in PBS+Tween.
  • PBS phosphate buffer saline
  • Tween 20 PBS+Tween
  • the HA binding protein bound to these wells was quantitated using an avidin- biotin detection system and ABTS (2,2' azino-bis(3-ethyl-benzthiazolin-6-sulfonic acid)) substrate (Vector Laboratories, Burlingame, Calif).
  • a standard graph can be prepared by plotting absorbance (405 nm) versus human umbilical cord HA concentrations (ng/ml). Using this graph, the HA concentration in each dilution of the urine specimen may be calculated. From several such determinations, the mean HA concentration in each sample was determined and then normalized to the creatinine concentration (mg/ml) in the urine sample.
  • HA assay of the invention has been shown to detect bladder cancer at a sensitivity of about 88% using a cut-off limit of approximately 500 ng/ml. Lokeshwar, et al. Methods for detection and evaluation of bladder cancer United States Patent 6,350,571 . Although it is not necessary to understand the mechanism of an invention, it is believed that cut-off limits of HA concentration may vary, and the population spread must be taken into consideration. Setting the cut-off limit of HA concentration to arrive at appropriate predictors for long-term dialysis may involve considering factors including, but not limited to, age, diet, concentration of protein in the sample, environmental influence, genetic background, hydration status, medical history, physical condition, sex, weight, or the like.
  • the HA assay comprises adsorbing HA onto the surface of a solid phase.
  • the solid phase can be any conventional solid phase, including nitrocellulose and the like, and preferably microtiter wells.
  • the surface of the solid phase is preferably washed using conventional buffer(s). Because the solid phase still has sites left on its surface which are capable of coupling with the HA or other molecules, it is preferred that prior to addition of the sample a blocking substance be added so as to cover any part of the solid phase on which the HA has not been adsorbed. Examples of suitable blocking substances include ⁇ -globulin and albumin derived from cows or other animals. Bovine serum albumin is preferred. After blocking the free sites of the solid phase, the surface of the solid phase is preferably washed using conventional buffer(s).
  • HA binding protein HA binding protein
  • the incubation time and conditions can vary within wide limits, but an incubation time of about 4 to about 16 hours, and an incubation temperature of about 4°C to about 37°C is satisfactory. Nonetheless, longer or shorter incubation times and higher or lower incubation temperatures are also possible.
  • HABP suitable for use with the assays of this invention can be readily purified from a number of sources, such as bovine nasal cartilage ( Tengblad, Biochim. Biophys. Acta, 578: 281-289, 1979 ), pig laryngal cartilage ( Fosang et al., Matrix, 10: 306-313, 1990 ).
  • bovine nasal cartilage Tengblad, Biochim. Biophys. Acta, 578: 281-289, 1979
  • pig laryngal cartilage Fosang et al., Matrix, 10: 306-313, 1990 .
  • the HABP is biotinylated, and the bound HABP is visualized following incubation with an avidin-enzyme conjugate and any substrate for the enzyme which generates a colored product.
  • an avidin-enzyme conjugate i.e., avidin-enzyme conjugate
  • any substrate for the enzyme which generates a colored product i.e., avidin-enzyme conjugate
  • an avidin-enzyme conjugate i.e., avidin-enzyme conjugate
  • any substrate for the enzyme which generates a colored product i.e., enzyme molecules
  • the signal i.e., colored product
  • any conventional marker system may be used in conjunction with the HABP.
  • Suitable marker systems include enzymes, fluorescence, chemiluminescence, enzyme-substrate, isotope markers, radiolabels and the like.
  • the determination of the amount of HABP bound to the HA coated on the solid support is via an avidin-biotin detection system.
  • Another useful marker system employs keratin sulfate and keratin sulfate-reactive antibodies.
  • the urinary HA levels can usefully be determined using a microtiter plate reader, and can be extrapolated from a standard graph. The amount of HABP coupled with the coated HA can then be correlated with the existence of bladder cancer in the patient from whom the sample of biological fluid was collected.
  • purified hyaluronic acid is preferably used as a standard.
  • the HA-binding fragments used in the above assay may be isolated from human umbilical cord HA (.about.500 mg) by digestion with 20,000 units of testicular hyaluronidase (Sigma Chemical Co., St. Louis, Mo.), at 37°C. for different time intervals. The HA fragments generated were separated on a Sephadex G-50 column (1.5 x 120 cm). Ten ml fractions were collected and assayed for the uronic acid content ( Bitter and Muir, A modified uronic acid carbazole reaction. Anal. Biochem., 4:330-334, 1962 ). The fractions were combined to give three preparations, F1, F2 and F3.
  • the number of reducing ends in each fraction was determined by the Dygert assay ( Dygert et al., Determination of reducing sugars with improved precision. Anal. Biochem., 13: 367-374, 1965 ). Since each linear polysaccharide of HA or its fragment contains a single reducing end, the chain length of each fragment was calculated from the number of reducing ends per mole of uronic acid. The size range of oligosaccharides in each fraction was also determined by incorporating 3 H labeled HA (prepared as described in Lokeshwar et al., Ankyrin binding domain of CD44(GP85) is required for the expression of hyaluronic acid-mediated adhesion function. J. Cell Biol., 126 1099-1109, 1994 ) during HA digestion and analyzing the fragments by gel electrophoresis and fluorography.
  • long-term dialysis may be predicted by quantitatively measuring HA in a sample of biological fluid (such as, for instance, a urine specimen) collected from a patient suspected of having a kidney injury and/or disease.
  • a sample of biological fluid such as, for instance, a urine specimen
  • Any conventional assay methodology can be used to determine the presence and measurement of HA, including radioassays, sandwich assays, inhibition assays and the like.
  • HA is preferably measured a competitive binding assay. More preferably, the assay of the invention works in the same manner as an ELISA test, but does not make use of antibody completing mechanisms.
  • long-term dialysis can be predicted using a method, comprising:
  • the method may further comprise detecting a signal associated with, or produced by, the bound HABP.
  • a signal associated with, or produced by, the bound HABP may be used to determine therefrom the amount of HA present in the sample.
  • a microtiter plate reader can be used to measure absorbance of colored product as an indirect measure of biotinylated HABP bound to the solid support (e.g., an avidin-enzyme conjugate and labeled substrate are used to generate the colored product).
  • the maximum absorbance can be obtained by incubating the HA-coated wells with buffer alone in the absence of any HA or HA-containing sample.
  • a standard graph can then be prepared by plotting absorbance versus ng/well or 0.2 ml of HA. Using this standard graph, the HA concentration (ng/ml) in each dilution of the sample can be calculated. From several such determinations the mean HA concentration in each sample can be determined. Creatinine concentration can be determined such that the HA concentrations can be normalized.
  • predicting whether a patient will required long-term dialysis may be determined by the following calculations derived from normalized urinary HA level: HA (ng/ml) extrapolated from a time course graph x dilution factor/mg/ml urinary protein. For example, a low absorbance reading would be indicative of a significant amount of HA in the urine sample, which would itself be indicative of the need for long-term dialysis in the patient.
  • Urine specimens from normal subjects and patients may be concentrated 10-fold and dialyzed extensively against PBS. Approximately 2 ml of each of the dialyzed specimens (about.20 mg protein) was applied to a Sepharose 6 CL-B column (1.5 x 120 cm) (Pharmacia, Piscataway, N.J.) equilibrated with PBS. The column was run in PBS at 7 ml/hr and 3.5 ml fractions were collected. The fractions were assayed for HA by the ELISA-like assay as described above.
  • the column was calibrated using human umbilical vein HA (Mr.about.2 x 10 6 D) and the HA fragments, F1, F2 and F3.
  • the ELISA-like assay may involve the use of a biotinylated HA binding protein to determine the HA concentration in urine specimens. Because urinary HA levels (i.e., normally in ng quantities) are found to be influenced by the hydration status and urine output, these levels were normalized to urinary creatinine content.
  • Hyaluronidase is an endoglycosidic enzyme that degrades HA by hydrolyzing the N-acetylglucosaminic bonds in HA.
  • the limited degradation of HA by hyaluronidase results in the generation of HA fragments of specific lengths (.about.3-25 disaccharide units) that are angiogenic ( West et al., Angiogenesis induced by degradation products of hyaluronic acid. Science, 228: 1324-1326, 1985 ).
  • hyaluronidases can be categorized into two classes, those active at neutral pH (pH optimum 5.0), and those active at acidic pH (pH 3.5- 4.0) ( Roden et al., Enzymatic pathways of hyaluronan catabolism. In: The Biology of hyaluronan, (J. Whelan, ed.), pp. 60-86, New York, Wiley Chichister (Ciba Foundation Symposium 143), 1989 ; West et al., ibid.; Gold, Purification and properties of hyaluronidase from human liver. Biochem.
  • the invention contemplates the use of hyaluronic acid binding protein in the manufacture of a diagnostic kit for predicting long-term dialysis.
  • the kit may comprise HA and/or HAase, HABP and a marker or HABP conjugated to a marker, and ancillary reagents suitable for use in detecting the presence of HA and/or HAase in a biological sample (i.e., for example, a urine sample).
  • a biological sample i.e., for example, a urine sample.
  • An example of a diagnostic kit contemplated by this invention is a conventional dipstick test device.
  • a dipstick test device may support an HA assay to predict long-term dialysis.
  • a solid phase in the form of a dipstick can be used to assay HA, as described above.
  • the dipstick can be coated or impregnated with HA, wherein the dipstick may be used to test any biological fluid, including but not limited to urine.
  • Hyaluronic acid was determined in human urine as described above.
  • a time course was generated by collecting and analyzing HA in urine for two weeks (i.e., fourteen days; D1-D14).
  • R28 recovering patients
  • NR28 non-recovering patients
  • the data in this example examines the differences between the normalized absolute hyaluronic acid levels above samples taken on D1, D7, and/or D14 after kidney injury collected in accordance with Example 1 for patients showing recovery at both twenty-eight days (R28) and sixty days (R60) past kidney injury, and non-recovering patients (NR28 and NR60).
  • This example replots the data in accordance with Example 2 to further illustrate the magnitude of the differences between recovering patients and non-recovering patients.
  • the data is expressed as a percentage (i.e., D7 ⁇ D1, D14 ⁇ D1, D7 ⁇ D14, or D14 ⁇ D7).

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